The present invention provides tetracyclic 1,2,3,4,5,6-hexahydroazepino-[4,5-b]indole derivatives having a ring connecting position 6 (N-6) and position 7 (C-7), and more specifically, provides compounds of formula (I) described hereinbelow. These compounds are 5-HT ligands, and are useful for treating diseases wherein modulation of 5-HT activity is desired.
Serotonin has been implicated in a number of diseases and conditions which originate in the central nervous system. These include diseases and conditions related to sleeping, eating, perceiving pain, controlling body temperature, controlling blood pressure, depression, anxiety, schizophrenia, and other bodily states. R. W. Fuller, Biology of Serotonergic Transmission, 221 (1982); D. J. Boullin, Serotonin in Mental Abnormalities 1:316 (1978); J. Barchas, et al., Serotonin and Behavior, (1973). Serotonin also plays an important role in peripheral systems, such as the gastrointestinal system, where it has been found to mediate a variety of contractile, secretory, and electrophysiologic effects.
As a result of the broad distribution of serotonin within the body, there is a tremendous interest in drugs that affect serotonergic systems. In particular, receptor-specific agonists and antagonists are of interest for the treatment of a wide range of disorders, including anxiety, depression, hypertension, migraine, obesity, compulsive disorders, schizophrenia, autism, neurodegenerative disorders (e.g. Alzheimer""s disease, Parkinsonism, and Huntington""s chorea), and chemotherapy-induced vomiting. M. D. Gershon, et al., The Peripheral Actions of 5-Hydroxytryptamine, 246 (1989); P. R. Saxena, et al., Journal of Cardiovascular Pharmacology, 15:Supplement 7 (1990).
The major classes of serotonin receptors (5-HT1-7) contain fourteen to eighteen separate receptors that have been formally classified. See Glennon, et al., Neuroscience and Behavioral Reviews, 1990, 14, 35; and D. Hoyer, et al. Pharmacol. Rev. 1994, 46, 157-203. Recently discovered information regarding subtype identity, distribution, structure, and function suggests that it is possible to identify novel, subtype specific agents, having improved therapeutic profiles (e.g. fewer side effects).
For example, the 5-HT2 family of receptors is comprised of 5-HT2A, 5-HT2B, and 5-HT2C subtypes, which have been grouped together on the basis of primary structure, secondary messenger system, and operational profile. All three subtypes are G-protein coupled, activate phospholipase C as a principal transduction mechanism, and contain a seven-transmembrane domain structure. There are distinct differences in the distribution of the three 5-HT2 subtypes. The 5-HT2B and 5-HT2A receptors are widely distributed in the periphery, while the 5-HT2C receptor has been found only in the central nervous system, being highly expressed in many regions of the human brain. See G. Baxter, et al. Trends in Pharmacol. Sci. 1995, 16, 105-110.
Subtype 5-HT2A has been associated with effects including vasoconstriction, platelet aggregation, and bronchoconstriction, while subtype 5-HT2C has been associated with diseases that include depression, anxiety, obsessive compulsive disorder, panic disorders, phobias, psychiatric syndromes, and obesity. Very little is known about the pharmacologic role of the 5-HT2B receptor. See F. Jenck, et al., Exp. Opin. Invest. Drugs, 1998, 7, 1587-1599; M. Bos, et al., J. Med. Chem., 1997, 40, 2762-2769; J. R. Martin, et al., The Journal of Pharmacology and Experimental Therapeutics, 1998, 286, 913-924; S. M. Bromidge, et al., J. Med. Chem., 1998, 41, 1598-1612; G. A. Kennett, Drugs, 1998, 1, 4, 456-470; and A. Dekeyne, et al., Neuropharmacology, 1999, 38, 415-423.
U.S. Pat. No. 3,676,558, issued Jul. 11, 1972, discloses compositions comprising specific 6-alkyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole compounds. The compositions are reported to be useful to suppress hunger in mammals. This patent also discloses a method for inducing anorexia in obese subjects to produce weight loss. The azepino[4,5-b]indole compounds disclosed in this patent lack the ring connecting the 6-position and the 7-position that is present in the compounds of the instant invention.
U.S. Pat. No. 3,839,357, issued Oct. 1, 1974, discloses specific 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole compounds, which are reported to have sedative or tranquilizing action. The azepino[4,5-b]indole compounds disclosed in this patent also lack the ring connecting the 6-position and the 7-position that is present in the compounds of the instant invention.
There is currently a need for pharmaceutical agents that are useful to treat diseases and conditions that are associated with 5-HT receptors.
In accordance with the present invention, novel compounds which demonstrate useful biological activity, and particularly activity as 5-HT receptor ligands, are provided. Thus, the present invention provides a compound of formula I: 
wherein,
each R1 is independently hydroxy, nitro, halo, cyano, trifluoromethyl, trifluoromethoxy, C1-7alkyl, C1-7alkoxy, C1-7alkanoyl, C1-7alkoxycarbonyl, C1-7alkanoyloxy, aryl, heteroaryl, xe2x80x94S(O)mNRaRb, NRcRd, xe2x80x94S(O)mRe, or xe2x80x94C(xe2x95x90O)NRaRb, wherein any C1-7alkyl, C1-7alkoxy, C1-7alkanoyl, C1-7alkoxycarbonyl, or C1-7alkanoyloxy of R1 is optionally partially unsaturated and is optionally substituted with aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxy, nitro, halo, cyano, C1-7alkoxy, C1-7alkanoyl, C1-7alkoxycarbonyl, C1-7alkanoyloxy, xe2x80x94S(O)mRe, xe2x80x94S(O)mNRaRb, NRcRd, or xe2x80x94C(xe2x95x90O)NRaRb;
R2 is hydrogen, C1-7alkyl, C1-7alkanoyl, arylcarbonyl, aryl, (aryl)C1-7alkyl, C1-7alkoxycarbonyl, aryloxycarbonyl, arylsulfonyl, or (aryl)C1-7alkoxycarbonyl;
X and Y together are a 2, 3, or 4 membered saturated or partially unsaturated chain comprising one or more carbon atoms and optionally comprising one oxy (xe2x80x94Oxe2x80x94), thio (xe2x80x94Sxe2x80x94), sulfinyl (xe2x80x94SOxe2x80x94), sulfonyl (S(O)2xe2x80x94), or NRf in the chain; wherein the chain is optionally substituted on each carbon with oxo (xe2x95x90O), thioxo (xe2x95x90S), xe2x80x94NRqRr, xe2x80x94S(O)pRs, or xe2x80x94ORt, or with one or two substituents independently selected from the group consisting of C1-7alkyl, (C1-7alkoxy)C1-7alkyl, aryl, (aryl)C1-7alkyl, heteroaryl, (heteroaryl)C1-7alkyl, and (aryl)oxyC1-7alkyl; or wherein the chain is optionally substituted on a carbon with a 4, 5, or 6 membered spirocyclic carbon ring; or wherein the chain is optionally substituted on two adjacent atoms with a 2, 3, or 4 membered alkylene chain (e.g. xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2CH2CH2xe2x80x94, or xe2x80x94CH2CH2CH2CH2xe2x80x94) forming a ring that is fused to the ring comprising X and Y;
each m is independently 0, 1, or 2;
n is 0, 1, 2, or 3;
p is 0, 1, or 2;
each Ra and Rb is independently hydrogen, C1-7alkyl, aryl, (aryl)C1-7alkyl, heteroaryl, or (heteroaryl)C1-7alkyl; or Ra and Rb together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
each Rc and Rd is independently hydrogen, C1-7alkyl, C1-7alkanoyl, C1-7alkoxycarbonyl, aryl, (aryl)C1-7alkyl, heteroaryl, (heteroaryl)C1-7alkyl, arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl, or heteroaryloxycarbonyl; or Rc and Rd together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
each Re is independently hydrogen, C1-7alkyl, aryl, (aryl)C1-7alkyl, heteroaryl, or (heteroaryl)C1-7alkyl;
Rf is hydrogen, C1-7alkyl, aryl, (aryl)C1-7alkyl, heteroaryl, (heteroaryl)C1-7alkyl, or is a bond to a 2, 3, or 4 membered alkylene chain that forms a ring that is fused to the ring comprising X and Y;
each Rq and Rr is independently hydrogen, C1-7alkyl, aryl, (aryl)C1-7alkyl, heteroaryl, or (heteroaryl)C1-7alkyl; or Rq and Rr together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
Rs is C1-7alkyl, aryl, (aryl)C1-7alkyl, heteroaryl, or (heteroaryl)C1-7alkyl; and
Rt is hydrogen, C1-7alkyl, aryl, (aryl)C1-7alkyl, heteroaryl, or (heteroaryl)C1-7alkyl;
wherein any aryl or heteroaryl ring of R1, R2, X, Y, Ra-Rf, or Rq-Rt is optionally substituted with one or more (e.g. 1, 2, 3, or 4) substituents independently selected from halo, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, C1-7alkyl, C1-7alkoxy, phenyl, sulfonyl, NRjRk, or xe2x80x94C(xe2x95x90O)NRjRk; wherein each Rj and Rk is independently hydrogen, C1-7alkyl, C1-7alkanoyl, C1-7alkoxycarbonyl, aryl, (aryl)C1-7alkyl, arylcarbonyl, or aryloxycarbonyl; or Rj and Rk together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
or a pharmaceutically acceptable salt thereof;
provided Y is not oxy, thio, sulfinyl, or NRf; and
provided X and Y together are not a 2-membered unsaturated chain; and
provided no carbon of X and Y is bonded to more than one oxy, thio, sulfinyl, or NRf.
In another aspect, the present invention also provides:
a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient (the composition preferably comprises a therapeutically effective amount of the compound or salt),
a method for treating a disease or condition in a mammal (e.g. a human) wherein a 5-HT receptor is implicated and modulation of a 5-HT function is desired comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof to the mammal,
a method for treating or preventing a disease or disorder of the central nervous system in a mammal comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof to the mammal, and
a method for modulating 5-HT receptor function, comprising administering an effective modulatory amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.
The invention also provides novel intermediates and processes disclosed herein that are useful for preparing compounds of formula I.